Adverse drug side effects, such as cardiotoxicity, are a major concern in drug development and a major cause of drug withdrawal from the market. Therefore, cardiac safety testing of drug candidates is an important part of the drug discovery and development process. All new chemical compounds need to be subjected to preclinical assessment for cardiac liability, in particular for drug-induced ventricular arrhythmia.
A number of in vitro and in vivo assays have been established to assess the effect of candidate compounds on cardiac function. Preclinical safety studies have been described in particular for the human ether-a-go-go (hERG) channel that is involved in QT prolongation, a risk factor that may induce potentially fatal arrhythmia, known as torsade de pointes (TdP) (Brown, 2005). The current standard method for the study of interaction of pharmacological compounds with hERG is patch clamp analysis that records changes in the current density properties in heterologous cell expression systems. To date this is the single compulsory test, also known as the “hERG safety test”, for the evaluation of cardiotoxicity as required by the guidelines of the drug development (Cavero & Crumb, 2005).
The need for the evaluation of further cardiac risk factors during drug development in addition to hERG, led to additional drug screening assays, such as the recent introduction of xCELLigence RCTA Cardio System (AVEA Biosciences, San Diego and Roche Applied Science). The assay provides valuable information in regard to cardiotoxicity by monitoring the contractility of cardiomyocytes based on impedance measurements (Xi et al., 2011) and thus allows a cardio-safety assessment.
There is a need in the art for improved means and methods for cardio-safety assessment.